Tag: genetic disorder

Synchrotron light for deciphering Friedreich’s Ataxia

Synchrotron light for deciphering Friedreich’s Ataxia

A team from the Germans Trias i Pujol Research Institute (IGTP) in Badalona is performing an experiment at the ALBA Synchrotron to obtain for the first time 3D images of cells with this disease.

Friedreich’s ataxia affects more than 3,000 people in Spain, causing serious mobility problems and other severe illnesses such as heart disease. At present there is no treatment to prevent or cure the disease.

Friedreich’s ataxia is a rare neurodegenerative disease that progressively damages mobility, balance and coordination. It is an inherited disease, caused by a genetic mutation, that can appear when both parents are carriers. A research group from the Germans Trias i Pujol Research Institute (IGTP), at the Can Ruti Campus in Badalona, led by Dr. Antoni Matilla, is looking into the causes and possible treatments for this disease that results in high disability and an important decrease in the patients’ quality of life.

“Today there is no treatment or cure for Friedreich’s ataxia. It is necessary to try to understand how the disease develops in order to propose therapeutic solutions”, says Dr. Ivelisse Sánchez, co-Principal Investigator of this project at the Neurogenetics Unit of the IGTP. Researchers are now analysing donors’ cells in the ALBA Synchrotron to see the changes caused by the disease.

>Read more on the ALBA website

Image: Dr. Ivelisse Sánchez, co-Principal Investigator of the project, and pre-doctoral researcher Eudald Balagué at the MISTRAL beamline.

Structure reveals mechanism behind periodic paralysis

Structure reveals mechanism behind periodic paralysis

The results suggest possible drug designs that could provide relief to patients with a genetic disorder that causes them to be overcome suddenly with profound muscle weakness.

A rare genetic disorder called hypokalemic periodic paralysis (hypoPP) causes sudden, profound muscle weakness in people who occasionally exhibit low levels of potassium in their blood, or hypokalemia. When a patient is hypokalemic, hypoPP affects the function of the muscles responsible for skeletal movement. The disease has been known to stem from mutations in certain membrane proteins that channel and regulate the flow of sodium into cells. Exactly how the mutation affects the proteins’ function, however, was not known.

In earlier work, researchers from the Catterall Lab at the University of Washington had solved the structure of a sodium channel called NavAb from a prokaryote (single-celled organism). As a next step, the group decided to see if NavAb could serve as a model for studying the mutations that cause hypoPP in humans (eukaryotes), with the goal of finding a way to prevent or treat this disorder.

A leak in the pipe?

In a resting state, muscle-cell membranes keep potassium ions and sodium ions separated, inside and outside the cell, respectively, creating a voltage across the membrane. A chemical signal from a nerve cell sets off a cascade of events that results in sodium ions flowing into the cell, changing the membrane potential and and ultimately triggering muscle contraction.

>Read more on the Advanced Light Source website

Image: Three states of the voltage-sensing domain (VSD) of a membrane-channel protein. In the normal state, the water-accessible space (magenta) does not extend through the channel, preventing sodium (gray spheres) from passing through. In the disease state, a clear passage allows sodium to leak through, resulting in muscle paralysis. In the “rescued” state, the binding of guanidinium (blue and yellow spheres) effectively closes the channel and blocks sodium leakage. The red sphere represents the location of the disease-causing mutation. The side-chain sticks represent the voltage sensors of the sodium channel.